28 Chapter 2 2.5 DISCUSSION The present study aimed to investigate the association of cardiovascular risk factors and novel advanced WMH markers in non-demented older adults. We showed that the presence of hypertension was associated with a more irregular shape of periventricular/confluent WMH, but not with WMH volume. Presence of diabetes was associated with deep WMH volume. BMI or hyperlipidemia showed no association with WMH markers in our study. We found an association between hypertension and a more irregular WMH shape, but did not find an association with WMH volume. An association between hypertension and WMH volume has previously been shown in several large population-based studies focusing on older adults.16,17 Accordingly, hyper- tension is seen as one of the strongest cardiovascular risk factors associated with WMH. In our study—with a smaller sample size than other population-based studies—we did not find such an association. No previous studies have focused on the association between hypertension and WMH shape. The findings of our study might indicate that WMH shape is a more sensitive marker of hypertension-induced brain changes than WMH volume, since WMH shape was associated with hypertension while WMH volume was not. Based on the results of our study, we postulate that hypertension leads to distinct pathological changes within the small vessels of the brain, which manifest as a distinct WMH MRI phenotype. Hypertension has a direct destructive effect on small arteries, arterioles, venules and capillaries in the brain. Progressive pathological changes to the small vessels of the brain, induced by atheromas and micro-embolisms2,18, may manifest as distinct WMH phenotypes on MRI due to the anatomical macrostructure of the small vessels located around the ventricles in the white matter. This highlights the strong vascular component in WMH development already suggested in previous research.3,4 In our study each WMH shape marker that was analyzed represents a different spectrum of shape variations. For example, presence of hypertension is related to the variation in shape of periventricular/confluent WMH represented by a low convexity and high concavity index, but not to variations in shape represented by solidity or fractal dimension. Important to acknowledge in this regard is that convexity and the concavity index are mathematically related to each other. It is difficult to directly translate our described associations on a group-level to an individual patient in a clinical setting. For future translation to clinical practice, artificial intelligencebased models including a combination of several MRI biomarkers are required for more accurate applications in the field of diagnosis or prognosis. At present, the association between diabetes and WMH volume is not entirely understood. Previous studies in community-dwelling older individuals have shown associations of type 2 diabetes mellitus and total WMH volume19,20, while other cross-sectional studies in
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